Photosensitive and pH-dependent activity of pyrazine-functionalized carbazole derivative as promising antifungal and imaging agent

Abstract

Carbazole skeleton plays a significant role as a structural scaffold of many pharmacologically active compounds. Pyrazine-functionalized carbazole derivative was constructed by coupling 2-amino-5-bromo-3-methylaminepyrazine (ABMAP) into 3 and 6 positions of the carbazole ring. Multiexperimental methods were used, e.g., potentiometric, spectroscopic (ATR, UV, XRD powder, 1 H and 13 C NMR), electrochemical (cyclic voltammetry), and optical techniques, to receive the complete structural analysis, physicochemical (pKa, logP) and biological profile of a new carbazole derivative with acronym 3,6-PIRAMICAR. the interaction ability of the compound studied with potential cellular targets like Calf Thymus DNA (CT-DNA), or BovineSerumAlbumin (BSA) were also taken into account. experiments showed the existence of strong binding, but no DnA or BSA cleavage was observed. the comparative analyzes of compounds anti-Candida action clearly show pH-dependent antifungal activity of 3,6-PIRAMICAR , which was strongly stimulated in the acidic media. Surprisingly, the titled compound turn out to be much more effective (14 times by MIC50; 8 times by MIC; c.a. 4 times by MFC) against Candidakrusei than fluconazole at pH 4. The emergence of multidrug-resistant microorganisms, as well as fungal infectious diseases, is a major global problem, especially for immuno-deficient populations. The development of new antifungal agents in clinical trials is problematic inferior to the incidence of drug resistance, and the available antifungal agents are restricted. Their mechanisms are based on certain characteristics of the fungus in order to avoid biological similarities with the host 1. Fungi in the Candida genus are the most common fungal pathogens which can colonize various host niches (stomach, vagina and oral mucosa) with varying ambient pH range 2-6. Carbazoles and derivatives with carbazole skeleton are currently tested intensively according to their antimicrobial properties which is directly relating with their structure or in more details with anaromatic N-heterocyclic ring inside 7. Carbazole derivatives have been reported to be potential agents against tumor 8 or opportunistic infections of AIDS 9,10. The studies about high active DNA intercalators show the significance of the carbazole structural agents like planarity or aromaticity 11,12. Interestingly, the mentioned parameters are described as responsible for the high affinity of carbazoles substituted at 3,6-or 2,7-positions by amine, amidine, or imidazoline groups to GC or AT-rich sequences of DNA 13,14. However, chemistry of especially di-substituted 3,6-derivatives of carbazole is still not very extensively explored due to problems with synthesis of such compounds. Mainly nitrogen atom was a hot spot for carbazole derivatives 14. The first concept of the studies was to check the basic design structures assumptions to predict pharmaceuticals activity, like presented carbazole functionalized by pyrazines-our previous research objects. Consequently, the confirmation of the possibili...

Low-Molecular Pyrazine-Based DNA Binders: Physicochemical and Antimicrobial Properties

“…Our previous studies showed the high antifungal activity of pyrazine derivatives at a low pH, supporting their potential application as drugs for the treatment of vaginal and gastric mycoses [45]. Due to the development of high bacterial and fungal resistance to the known used therapeutics, we designed new pyrazine derivatives as potential antimicrobial drugs [46][47][48].…”

Anticancer Study on IrIII and RhIII Half-Sandwich Complexes with the Bipyridylsulfonamide Ligand

“…The association/binding constants of these interactions with CA were determined according to the Benesi–Hildebrand eq A 0 A − A 0 = ε G ε H − G − ε G + ε G ε H − G − ε G · 1 K b i n d false[ normalC normalA false] where A 0 and A are the absorbances of the acridine derivative in the absence and presence of CA, respectively; ε G and ε H–G are the absorption coefficients of the acridine derivative unbounded and its adduct with CA, respectively. Thus, the double reciprocal plot of A 0 /( A – A 0 ) vs 1/[CA] is linear and the binding constant ( K bind ) was estimated based on the linear fit parameters established as the ratio of the intercept to the slope. , …”

Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies

“…The different chloropyrazine-tethered pyrimidine derivatives (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were obtained by the condensation of chloropyrazinyl chalcones (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) with guanidine hydrochloride (Scheme 1) using a base catalyst (KOH) in yields ranging from 56-92%. The molecular structures of the chloropyrazine-tethered pyrimidine hybrids were disentangled using FT-IR and 1 H NMR spectral data and are presented in our previous paper [55].…”

“…Examples of drugs with a pyrimidine nucleus are antibacterial and antimalarial agents targeting the folate pathway: trimethoprim, iclaprim, sulfadimethoxine, pyrimethamine, and sulfadoxine; antimetabolite and ergosterol biosynthesis inhibitor antifungal drugs: flucytosine and voriconazole; antimetabolite anti-cancer agents: 5-fluorouracil and capecitabine; tyrosine kinase inhibitors: imatinib, dasatinib, and nilotinib; antivirals: ara-c, idoxuridine, zidovudine, stavudine, lamivudine, and emtricitabine; and the antitubercular drug capreomycin (Figure 1). Many substituted pyrazine derivatives were reported with potential antibacterial [6][7][8][9][10][11], antifungal [12][13][14][15], anticancer [16][17][18][19][20][21], antioxidant [22][23][24][25], and antitubercular [9,[26][27][28] activities. Similarly, pyrimidine-based compounds also showed excellent antimicrobial (antibacterial and antifungal) [29][30][31][32][33], antimycobacterial [34][35][36][37][38], antioxidant [39][40][41][42], cytotoxic and anticancer [42][43][44]…”